A recently discovered mechanism of inflammatory injury, the "poly (ADP-ribose) synthetase (PARS) pathway," has been implicated in the pathogenesis of various forms of inflammation. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. These processes trigger neutrophil infiltration into the inflammatory site. The applicants have developed a novel class of compounds with anti-inflammatory potential. In this proposal, the investigator presents evidence that a potent non-toxic PARS inhibitor, reduces oxidant-induced cellular injury. Furthermore, he presents evidence for the role of PARS in a rat model of uveitis. The specific aim of the present application is to perform definitive in vivo studies in a rat model of endotoxin-induced uveitis in order to test whether PARS inhibition can be developed for the experimental therapy of this condition. The results of the present application will permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA, and a phase I clinical trial. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE